Reviews

Patients with chronic lymphocytic leukemia (CLL) can have variable courses, from indolent disease to rapid progression with limited response to treatment. The Rai and Binet staging systems were the first to classify patients into prognostic categories. Newer prognostic markers that correlate with shorter time to progression and time to treatment include elevated serum β2M, TK, ZAP-70, and CD38, as well as unmutated IgVH. Abnormal cytogenetics are found in the majority of patients with CLL. Del(17p), as well as mutations of TP53, is associated with an aggressive clinical course and short overall survival. Nearly one-fifth of patients have del(11q) and have a significantly shorter median progression-free survival; mutations in the ATM gene, located on 11q, may also have adverse prognostic implications. Intermediate-risk cytogenetic findings include trisomy 12 and del(6q). Patients with del(17p) should be evaluated for novel agents and/or allogeneic stem cell transplantation in first remission. Patients with del(11q) require treatment with an alkylating agent in addition to nucleoside analogs and rituximab, and patients with trisomy 12q may express higher levels of CD20, thereby making the malignant cells more susceptible to biologic agents that target CD20. Despite advances in stratifying patients and improved chemoimmunotherapeutic regimens, additional research in prognostication and treatment is needed.

TABLE Poor Prognostic Features in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder characterized by monoclonal lymphocytosis. Between 2003 and 2008, the age-adjusted incidence rate was 4.2 per 100,000 persons per year, with an annual age-adjusted death rate of 1.5 per 100,000.[1] Although CLL has historically been considered an indolent, slow-growing disease, it progresses rapidly in some patients and they die within 2 to 3 years of diagnosis. Given the heterogeneous nature of the disease course, accurate predictors of prognosis are valuable for the clinical care and counseling of patients. The majority of patients are asymptomatic at the time of diagnosis, and use of a variety of prognostic measures can predict rapid disease progression and responses to treatment (Table). Although models for determining prognosis for patients with CLL have existed for over 35 years, these relied on simple clinical characteristics such as physical examination findings and blood counts. The complex biologic pathways in CLL are gradually being revealed, and the implications of abnormalities in these pathways, both for treatment and prognosis, are adding to our understanding of this heterogeneous disease.

Early Prognostic Classification Models

The first prognostic model was proposed in 1975 by Rai et al. The Rai staging system uses the presence or absence of lymphadenopathy, organomegaly, anemia, and thrombocytopenia to classify patients into one of five stages, stage 0 through stage IV. Median survival for these stages has been found to range from 19 months for stages III and IV to > 150 months for stage 0.[2].

The Binet staging system classifies patients into three categories based on the number of lymphoid tissues involved—including cervical, axillary, and inguinal lymph nodes, as well as liver and spleen—and the presence of anemia and/or thrombocytopenia. Group A patients have no thrombocytopenia or anemia and fewer than three lymphoid tissues involved, group B patients have no thrombocytopenia or anemia but three or more lymphoid tissues involved, and Group C patients have anemia and/or thrombocytopenia. Published median survival rates in these patients ranged from 2 years for patients in stage C to a survival similar to that of age-matched controls for patients in stage A.[3] However, these two staging systems examine patients' clinical status at a single point in time and cannot differentiate between indolent disease and disease that will subsequently become aggressive.

The lymphocyte doubling time, defined as the length of time it takes the absolute lymphocyte count to double from diagnosis, has also been found to have prognostic value in patients with CLL. In one study, those patients whose lymphocyte counts doubled in less than 12 months had a significantly shorter median survival (36 months), whereas those with a longer lymphocyte doubling time experienced longer overall survival (OS) (median survival was not reached).[4] Patterns seen on bone marrow examination also have prognostic value. A diffuse pattern of involvement, including destruction of normal bone marrow architecture and replacement of hematopoietic cells and fat cells with lymphocytes, was associated with decreased OS.[5] Lymphocyte doubling time requires serial blood measurements over time; in addition, the absolute lymphocyte count can vary as a result of other events unrelated to the malignancy. Bone marrow examination is invasive and requires a certain degree of subjectivity, and a diffuse pattern is more often seen in patients who present with already advanced disease. Therefore, these two prognostic factors have significant limitations.